PROJECT SUMMARY The aim of this proposal is to develop a small molecule suitable for long-term systemic administration to prevent/treat DR. Current standard of care for diabetic retinopathy (DR), or other ocular diseases with an obvious dysfunctional microvasculature basis, rely on treatment options that are inherently challenged with technical limitations and financial constraints. For example, high cost, requirement of specialized facilities, repetitive intravitreal injections, and limited patient responsiveness are some of the critical barriers to progress in care for DR. Hence, developing small molecules that can address one or more therapeutic targets by systemic administration will significantly improve various aspects of the current standard of care. As shown in FIELD and ACCORD clinical studies, long-term oral administration of Fenofibrate yielded promising clinical effects on DR, for which mechanism of action is attributed to activation of peroxisome proliferator- activated receptor-? (PPAR-?). However, clinical application of pharmacological activation of PPAR-? for DR still remains unexploited. The proposed research in Phase I will focus on evaluating the in vivo efficacy of A91, a novel PPAR-? selective agonist, in a diabetic animal model by examining the two important aspects of DR: vascular inflammation and vascular permeability. Aim 1 will study whether A91 can ameliorate inflammation in the retinal vasculature in diabetic condition, and Aim 2 will test its functional relevance by assessing the vascular permeability in the retina and visual acuity. Upon successful demonstration of its efficacy, Phase II studies will be proposed to further develop A91 as a potential therapeutic agent for DR.